Compounds and compositions for delivering active agents

ABSTRACT

Compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provide as well.

FIELD OF THE INVENTION

The present invention relates to compounds for delivering active agents,such as biologically or chemically active agents, to a target. Thesecompounds are well suited for forming non-covalent mixtures with activeagents for oral, intracolonic, pulmonary, or other routes ofadministration to animals. Methods for the preparation andadministration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

Conventional means for delivering active agents are often severelylimited by biological, chemical, and physical barriers. Typically, thesebarriers are imposed by the environment through which delivery occurs,the environment of the target for delivery, and/or the target itself.Biologically and chemically active agents are particularly vulnerable tosuch barriers.

In the delivery to animals of biologically active and chemically activepharmacological and therapeutic agents, barriers are imposed by thebody. Examples of physical barriers are the skin, lipid bi-layers andvarious organ membranes that are relatively impermeable to certainactive agents but must be traversed before reaching a target, such asthe circulatory system. Chemical barriers include, but are not limitedto, pH variations in the gastrointestinal (GI) tract and degradingenzymes.

These barriers are of particular significance in the design of oraldelivery systems. Oral delivery of many biologically or chemicallyactive agents would be the route of choice for administration to animalsif not for biological, chemical, and physical barriers. Among thenumerous agents which are not typically amenable to oral administrationare biologically or chemically active peptides, such as calcitonin andinsulin; polysaccharides, and in particular mucopolysaccharidesincluding, but not limited to, heparin; heparinoids; antibiotics; andother organic substances. These agents may be rapidly renderedineffective or destroyed in the gastro-intestinal tract by acidhydrolysis, enzymes, and the like. In addition, the size and structureof macromolecular drugs may prohibit absorption.

Earlier methods for orally administering vulnerable pharmacologicalagents have relied on the co-administration of adjuvants (e.g.,resorcinols and non-ionic surfactants such as polyoxyethylene oleylether and n-hexadecylpolyethylene ether) to increase artificially thepermeability of the intestinal walls, as well as the co-administrationof enzymatic inhibitors (e.g., pancreatic trypsin inhibitors,diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymaticdegradation. Liposomes have also been described as drug delivery systemsfor insulin and heparin. However, broad spectrum use of such drugdelivery systems is precluded because: (1) the systems require toxicamounts of adjuvants or inhibitors; (2) suitable low molecular weightcargos, i.e. active agents, are not available; (3) the systems exhibitpoor stability and inadequate shelf life; (4) the systems are difficultto manufacture; (5) the systems fail to protect the active agent(cargo); (6) the systems adversely alter the active agent; or (7) thesystems fail to allow or promote absorption of the active agent.

More recently, proteinoid microspheres have been used to deliverpharmaceuticals. For example, see U.S. Pat. No. 5,401,516, U.S. Pat. No.5,443,841 and U.S. Pat. No. RE35,862. In addition, certain modifiedamino acids have been used to deliver pharmaceuticals. See, e.g., U.S.Pat. No. 5,629,020; U.S. Pat. No. 5,643,957; U.S. Pat. No. 5,766,633;U.S. Pat. No. 5,776,888; and U.S. Pat. No. 5,866,536.

However, there is still a need for simple, inexpensive delivery systemswhich are easily prepared and which can deliver a broad range of activeagents by various routes.

SUMMARY OF THE INVENTION

Compounds and compositions that are useful in the delivery of activeagents are provided. The present invention encompasses compounds havingthe following formula, or salts thereof, or mixtures thereof.

The compositions of the present invention comprise at least one activeagent, preferably a biologically or chemically active agent, and atleast one of the compounds, or salts thereof, of the present invention.Methods for the preparation and administration of such compositions arealso provided.

Also provided are dosage unit forms comprising the compositions. Thedosage unit form may be in the form of a solid (such as a tablet,capsule or particle such as a powder or sachet) or a liquid.

Methods for administering a biologically active agent to an animal inneed of the agent, especially by the oral, intracolonic or pulmonaryroutes, with the compositions of the present invention, are alsoprovided, as well as methods of treatment using such compositions. Amethod of treating a disease in an animal comprising administering acomposition of the present invention to the animal in need thereof isprovided.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

The compounds may be in the form of the carboxylic acid and/or theirsalts. Salts include but are not limited to organic and inorganic salts,for example alkali-metal salts, such as sodium, potassium and lithium;alkaline-earth metal salts, such as magnesium, calcium or barium;ammonium salts; basic amino acids such as lysine or arginine; andorganic amines, such as dimethylamine or pyridine. Preferably, the saltsare sodium salts. The salts may be mono- or multi-valent salts, such asmonosodium salts and di-sodium salts. The salts may also be solvatesincluding ethanol solvates.

In addition, poly amino acids and peptides comprising one or more ofthese compound may be used.

An amino acid is any carboxylic acid having at least one free aminegroup and includes naturally occurring and synthetic amino acids. Polyamino acids are either peptides (which are two or more amino acidsjoined by a peptide bond) or are two or more amino acids linked by abond formed by other groups which can be linked by, e.g., an ester or ananhydride linkage. Peptides can vary in length from dipeptides with twoamino acids to polypeptides with several hundred amino acids. One ormore of the amino acids or peptide units may be acylated or sulfonated.

The compounds described herein may be derived from amino acids and canbe readily prepared from amino acids by methods within the skill ofthose in the art based upon the present disclosure and the methodsdescribed in WO96/30036, WO97/36480, U.S. Pat. No. 5,643,957 and U.S.Pat. No. 5,650,386. For example, the compounds may be prepared byreacting the single amino acid with the appropriate acylating oramine-modifying agent, which reacts with a free amino moiety present inthe amino acid to form amides. Protecting groups may be used to avoidunwanted side reactions as would be known to those skilled in the art.With regard to protecting groups, reference is made to T. W. Greene,Protecting Groups in Organic Synthesis, Wiley, N.Y. (1981), thedisclosure of which is hereby incorporated herein by reference.

Salts of the present compound may be made by methods known in the art.For example, sodium salts may be made by dissolving the compound inethanol and adding aqueous sodium hydroxide.

The compound may be purified by recrystallization or by fractionation onone or more solid chromatographic supports, alone or linked in tandem.Suitable recrystallization solvent systems include, but are not limitedto, acetonitrile, methanol, and tetrahydrofuran. Fractionation may beperformed on a suitable chromatographic support such as alumina, usingmethanol/n-propanol mixtures as the mobile phase; reverse phasechromatography using trifluoroacetic acid/acetonitrile mixtures as themobile phase; and ion exchange chromatography using water or anappropriate buffer as the mobile phase. When anion exchangechromatography is performed, preferably a 0-500 mM sodium chloridegradient is employed.

According to one embodiment, the compound is employed in its anhydrousform.

Active Agents

Active agents suitable for use in the present invention includebiologically active agents and chemically active agents, including, butnot limited to, pesticides, pharmacological agents, and therapeuticagents.

For example, biologically or chemically active agents suitable for usein the present invention include, but are not limited to, proteins;polypeptides; peptides; hormones; polysaccharides, and particularlymixtures of muco-polysaccharides; carbohydrates; lipids; other organiccompounds; and particularly compounds which by themselves do not pass(or which pass only a fraction of the administered dose) through thegastro-intestinal mucosa and/or are susceptible to chemical cleavage byacids and enzymes in the gastro-intestinal tract; or any combinationthereof.

Further examples include, but are not limited to, the following,including synthetic, natural or recombinant sources thereof: growthhormones, including human growth hormones (hGH), recombinant humangrowth hormones (rhGH), bovine growth hormones, and porcine growthhormones; growth hormone-releasing hormones; interferons, including α, βand γ; interleukin-1; interleukin-2; insulin, including porcine, bovine,human, and human recombinant, optionally having counter ions includingsodium, zinc, calcium and ammonium; insulin-like growth factor,including IGF-1; heparin, including unfractionated heparin, heparinoids,dermatans, chondroitins, low molecular weight heparin, very lowmolecular weight heparin and ultra low molecular weight heparin;calcitonin, including salmon, eel, porcine and human; erythropoietin;atrial naturetic factor; antigens; monoclonal antibodies; somatostatin;protease inhibitors; adrenocorticotropin, gonadotropin releasinghormone; oxytocin; leutinizing-hormone-releasing-hormone; folliclestimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim;prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroidhormone (PTH), including its fragments; antimicrobials, includinganti-fungal agents; vitamins; analogs, fragments, mimetics orpolyethylene glycol (PEG)-modified derivatives of these compounds; orany combination thereof. Other suitable forms of insulin, including, butnot limited to, synthetic forms of insulin, are described in U.S. Pat.Nos. 4,421,685, 5,474,978, and 5,534,488, each of which is herebyincorporated by reference in its entirety.

Delivery Systems

The compositions of the present invention comprise a delivery agent andone or more active agents. In one embodiment, one or more of thedelivery agent compounds, or salts of these compounds, or poly aminoacids or peptides of which these compounds or salts form one or more ofthe units thereof, may be used as a delivery agent by mixing with theactive agent prior to administration.

The administration compositions may be in the form of a liquid. Thedosing vehicle may be water (for example, for salmon calcitonin,parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol(for example, for heparin) and phosphate buffer (for example, for rhGH).Other dosing vehicles include polyethylene glycols, sorbitol, maltitol,and sucrose. Dosing solutions may be prepared by mixing a solution ofthe delivery agent compound with a solution of the active agent, justprior to administration. Alternately, a solution of the delivery agent(or active agent) may be mixed with the solid form of the active agent(or delivery agent). The delivery agent compound and the active agentmay also be mixed as dry powders. The delivery agent compound and theactive agent can also be admixed during the manufacturing process.

The dosing solutions may optionally contain additives such as phosphatebuffer salts, citric acid, glycols, or other dispersing agents.Stabilizing additives may be incorporated into the solution, preferablyat a concentration ranging between about 0.1 and 20% (w/v).

The administration compositions may alternately be in the form of asolid, such as a tablet, capsule or particle, such as a powder orsachet. Solid dosage forms may be prepared by mixing the solid form ofthe compound with the solid form of the active agent. Alternately, asolid may be obtained from a solution of compound and active agent bymethods known in the art, such as freeze drying, precipitation,crystallization and solid dispersion.

The administration compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds such as actinonin or epiactinonin andderivatives thereof. Other enzyme inhibitors include, but are notlimited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

The amount of active agent used in an administration composition of thepresent invention is an amount effective to accomplish the purpose ofthe particular active agent for the target indication. The amount ofactive agent in the compositions typically is a pharmacologically,biologically, therapeutically, or chemically effective amount. However,the amount can be less than that amount when the composition is used ina dosage unit form because the dosage unit form may contain a pluralityof compound/active agent compositions or may contain a dividedpharmacologically, biologically, therapeutically, or chemicallyeffective amount. The total effective amount can then be administered incumulative units containing, in total, an effective amount of the activeagent.

The total amount of active agent to be used can be determined by methodsknown to those skilled in the art. However, because the compositions maydeliver active agents more efficiently than prior compositions, loweramounts of biologically or chemically active agents than those used inprior dosage unit forms or delivery systems can be administered to thesubject, while still achieving the same blood levels and/or therapeuticeffects.

The presently disclosed compounds deliver biologically and chemicallyactive agents, particularly in oral, intranasal, sublingual,intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal,mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous,intramuscular and ocular systems, as well as traversing the blood-brainbarrier.

Dosage unit forms can also include any one or combination of excipients,diluents, disintegrants, lubricants, plasticizers, colorants,flavorants, taste-masking agents, sugars, sweeteners, salts, and dosingvehicles, including, but not limited to, water, 1,2-propane diol,ethanol, olive oil, or any combination thereof.

The compounds and compositions of the subject invention are useful foradministering biologically or chemically active agents to any animals,including but not limited to birds such as chickens; mammals, such asrodents, cows, pigs, dogs, cats, primates, and particularly humans; andinsects.

The system is particularly advantageous for delivering chemically orbiologically active agents that would otherwise be destroyed or renderedless effective by conditions encountered before the active agent reachesits target zone (i.e. the area in which the active agent of the deliverycomposition is to be released) and within the body of the animal towhich they are administered. Particularly, the compounds andcompositions of the present invention are useful in orally administeringactive agents, especially those that are not ordinarily orallydeliverable, or those for which improved delivery is desired.

The compositions comprising the compounds and active agents have utilityin the delivery of active agents to selected biological systems and inan increased or improved bioavailability of the active agent compared toadministration of the active agent without the delivery agent. Deliverycan be improved by delivering more active agent over a period of time,or in delivering active agent in a particular time period (such as toeffect quicker or delayed delivery) or over a period of time (such assustained delivery).

Following administration, the active agent present in the composition ordosage unit form is taken up into the circulation. The bioavailabilityof the agent is readily assessed by measuring a known pharmacologicalactivity in blood, e.g. an increase in blood clotting time caused byheparin, or a decrease in circulating calcium levels caused bycalcitonin. Alternately, the circulating levels of the active agentitself can be measured directly.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention without limitation. Allparts are given by weight unless otherwise indicated.

EXAMPLE 1 Compound Preparation

1a. Preparation of Compound 1.

4-Chlorosalicylic acid (10.0 g, 0.0579 mol) was added to a one-neck 250ml round-bottomed flask containing about 50 ml methylene chloride.Stirring was begun and continued for the remainder of the reaction.Coupling agent 1,1-carbonyldiimidazole (9.39 g, 0.0579 mol) was added asa solid in portions to the flask. The reaction was stirred at roomtemperature for approximately 20 minutes after all of the coupling agenthad been added and then ethyl-4-aminobutyrate hydrochloride (9.7 g,0.0579 mol) was added to the flask with stirring. Triethylamine (10.49ml, 0.0752 mol) was added dropwise from an addition funnel. The additionfunnel was rinsed with methylene chloride. The reaction was allowed tostir at room temperature overnight.

The reaction was poured into a separatory funnel and washed with 2N HCland an emulsion formed. The emulsion was left standing for two days. Theemulsion was then filtered through celite in a fritted glass funnel. Thefiltrate was put back in a separatory funnel to separate the layers. Theorganic layer was dried over sodium sulfate, which was then filtered offand the filtrate concentrated by rotary evaporation. The resulting solidmaterial was hydrolyzed with 2N NaOH, stored overnight underrefrigeration, and then hydrolyzing resumed. The solution was acidifiedwith 2N HCl and the solids that formed were isolated, dried undervacuum, and recrystallized twice using methanol/water. Solidsprecipitated out overnight and were isolated and dried. The solids weredissolved in 2N NaOH and the pH of the sample was brought to pH 5 with2N HCl. The solids were collected and HPLC revealed a single peak. Thesesolids were then recrystallized in methanol/water, isolated, and thendried under vacuum, yielding 4.96 g (33.0%) of 4-(4chloro-2-hydroxybenzoyl)aminobutyric acid. (C₁₁H₁₂ClNO₄; Molecularweight 257.67.) Melting point: 131-133° C. Combustion analysis: % C:51.27(calc.), 51.27 (found); % H: 4.69 (calc.), 4.55 (found); % N: 5.44(calc.), 5.30 (found). H NMR Analysis: (d₆-DMSO): δ 13.0, s, 1H (COOH);δ 12.1, s, 1H (OH); δ 8.9, t, 1H (NH); δ 7.86, d, 1H (H ortho to amide);δ 6.98, d, 1H (H ortho to phenol OH); δ 6.96, d, 1H, (H meta to amide);δ 3.33, m, 2H (CH₂ adjacent to NH); δ 2.28, t, 2H (CH₂ adjacent toCOOH); 67 1.80, m, 2H (aliphatic CH₂ beta to NH and CH₂ beta to COOH)

1b. Additional Preparation of Compound 1.

4-Chlorosalicylic acid (25.0 g, 0.1448 mol) was added to a one-neck 250ml round-bottomed flask containing about 75-100 ml methylene chloride.Stirring was begun and continued to the remainder of the reaction.Coupling agent 1,1-carbonyldiimidazole (23.5 g, 0.1448 mol) was added asa solid in portions to the flask. The reaction was stirred at roomtemperature for approximately 20 minutes after all of the coupling agenthad been added and then ethyl-4-aminobutyrate hydrochloride (24.3 g0.1448 mol) was added to the flask with stirring. Triethylamine (26.0ml, 0.18824 mol) was added dropwise from an addition funnel. Theaddition funnel was rinsed with methylene chloride. The reaction wasallowed to stir at room temperature overnight.

The reaction was poured into a separatory funnel and washed with 2N HCland an emulsion formed. The emulsion was filtered through celite in afritted glass funnel. The filtrate was put back in a separatory funnelto separate the layers. The organic layer was washed with water andbrine, then dried over sodium sulfate, which was then filtered off andthe filtrate concentrated by rotary evaporation. The resulting solidmaterial was hydrolyzed with 2N NaOH overnight. The solution wasacidified with 2N HCl and the brown solids that formed wererecrystallized using methanol/water, hot filtering off insoluble blackmaterial. White solids precipitated out and were isolated and dried,yielding 11.68 g (37.0%)of 4-(4 chloro-2-hydroxybenzoyl)aminobutyricacid. (C₁₁H₁₂ClNO₄; Molecular weight 257.67.) Melting point: 129-133° C.Combustion analysis: % C: 51.27(calc.), 51.26 (found); % H: 4.69(calc.), 4.75 (found); % N: 5.44 (calc.), 5.32 (found). H NMR Analysis:(d₆-DMSO): δ 13.0, s, 1H (COOH); δ 12.1, s, 1H (OH); δ 8.9, t, 1H (NH);δ 7.86, d, 1H (H ortho to amide); 67 6.98, d, 1H (H ortho to phenol OH);δ 6.96, d, 1H, (H meta to amide); δ 3.33, m, 2H (CH₂ adjacent to NH); δ2.28, t, 2H (CH₂ adjacent to COOH); δ 1.80, m, 2H (aliphatic CH₂ beta toNH and CH₂ beta to COOH).

1c. Additional Preparation of Compound 1

(4-[(4-Chloro-2-hydroxybenzoyl)amino]butanoic acid)

A 22 L, five neck, round bottom flask was equipped with an overheadstirrer, 1 L Dean-Stark trap with reflux condenser, thermocoupletemperature read out, and heating mantle. The following reaction was rununder a dry nitrogen atmosphere. Reagent n-butanol (5000 mL) and4-chlorosalicylic acid (2000 g, 11.59 mol) were charged to the reactionflask. The Dean-Stark trap was filled with n-butanol (1000 mL).Concentrated sulfuric acid (50 g) was added. The reaction mixture washeated to reflux for approximately 120 hours. Approximately 206 mL waterwas collected in the trap during this time. The heating mantle wasremoved and the reaction mixture allowed to cool to ambient temperature.The Dean-Stark trap was drained and removed. Deionized water (1000 mL)was charged. The biphasic mixture was stirred for 10 minutes. Stirringwas stopped and the phases allowed to separate. The lower aqueous phasewas siphoned off and discarded. A 10 wt % aqueous solution of sodiumbicarbonate (1000 mL) was charged to the reaction mixture. The mixturewas stirred for 10 minutes. The reaction mixture was tested with pHpaper to ensure the pH of the solution was greater than 7. Water (500mL) was added to the reaction mixture. The stirring was stopped and thephases allowed to separate. The lower aqueous layer was siphoned off anddiscarded. The reaction mixture was washed with another 500 mL portionof deionized water. The reactor was set up for atmospheric distillationinto a tared 5 L receiver. The mixture was distilled until the pottemperature rose to between 140 and 150° C. The distillation wasswitched from atmospheric distillation to vacuum distillation. Thepressure in the distillation setup was slowly lowered to 100 mmHg. Thepot temperature fell and the remaining n-butanol and n-butyl ether (areaction byproduct) distilled off. The heating was stopped and thereaction mixture allowed to cool to ambient temperature. The vacuum wasbroken with dry nitrogen. The crude butyl ester was transferred to a 5 Lpot flask of a vacuum distillation setup. The crude butyl ester wasdistilled at a pressure between 0.2 and 0.5 mmHg. The forerun collectedat a head temperature of <40° C. was discarded. The butyl4-chloro-2-hydroxybenzoate fraction was collected at a head temperaturebetween 104 and 112° C. This fraction had a weight of 2559 g. The yieldwas 96%.

A 22 L, five neck, round bottom flask was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, and aheating mantle. The reactor was purged with nitrogen. Butyl4-chloro-2-hydroxybenzoate (2559 g, 11.2 moles) and reagent methanol(10,000 mL) were charged to the reaction flask, and the contents werestirred until a solution was obtained. The reaction mixture was filteredthrough a Buchner funnel and returned to the reactor. The stirring ratewas increased, and gaseous ammonia was added rapidly to the headspace ofthe reactor. The ammonia gas addition was continued until thetemperature of the reactor reached 45° C. The addition of the ammoniawas suspended and the agitation rate lowered. The reaction was allowedto cool to ambient temperature. Ammonia gas addition, as describedabove, was repeated until the reaction was complete as indicated byliquid chromatography. Seven ammonia charges over five days were neededto complete the reaction. Approximately half of the solvent was removedby atmospheric distillation. The reaction mixture was cooled to ambienttemperature and 5 L of deionized water was added. Concentratedhydrochloric acid (approximately 500 mL) was added slowly to the reactoruntil the pH of the reaction mixture was between 4 and 5. The resultingprecipitate was collected by vacuum filtration through a large sinteredglass funnel. The product filter cake was washed with 2000 mL ofdeionized water, and dried at 50° C. for 32 hours to give 1797 g of4-chloro-2-hydroxybenzamide. The yield was 94%.

A 22 L, five neck, round bottom flask was equipped with an overheadstirrer, reflux condenser, addition funnel, thermocouple temperatureread out, and a heating mantle. The reactor was purged with nitrogen.Acetonitrile (4700 mL) and 4-chloro-2-hydroxybenzamide (1782 g, 10.4mol) were charged to the reaction flask and the stirring was started.Pyridine (1133 mL, 14.0 mol) was charged to the reactor. The resultingreaction slurry was cooled to less than 10° C. with an ice bath. Ethylchloroformate (1091 mL, 1237 g, 11.4 mol) was placed in the additionfunnel and charged slowly to the stirred reaction mixture such that thetemperature of the reaction mixture did not exceed 15° C. during theaddition. The temperature of the reaction mixture was held between 10and 15° C. for 30 minutes after the ethyl chloroformate addition wascomplete. The ice bath was removed, and the reaction mixture was warmedto ambient temperature. The reaction mixture was then slowly heated toreflux and held at that temperature for 18 hours. Liquid chromatographicanalysis of the reaction mixture indicated that the reaction was only80% complete. Approximately half of the solvent was removed byatmospheric distillation. The reaction mixture was cooled first toambient temperature and then to <10° C. with an ice bath. Additionalpyridine (215 mL, 2.65 mol) was added to the reaction mixture. Ethylchloroformate (235 g, 2.17 mol) was added slowly via an addition funnelto the cold reaction mixture. The reaction mixture was held between 10and 15° C. for 30 minutes after the ethyl chloroformate addition wascomplete. The ice bath was removed, and the reaction mixture was warmedto ambient temperature. The reaction mixture was then slowly heated toreflux and held at that temperature for 18 hours, after which timeliquid chromatographic analysis indicated that the reaction wascomplete. The reaction mixture was cooled first to ambient temperatureand then to <10° C. with an ice bath. Water (1600 mL) was added slowlyvia an addition funnel and the resulting slurry held at <10° C. for 90minutes. The solid product was collected by vacuum filtration through alarge sintered glass funnel. The product filter cake was washed withdeionized water and vacuum dried at 50° C. for 18 hours to give 1914 gof 7-chloro-2H-1,3-benzoxazine-2,4(3H)-dione as a tan solid. The yieldwas 83%.

A 22 L, five neck, round bottom flask was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, andheating mantle. The following reaction was run under a dry nitrogenatmosphere. 7-Chloro-2H-1,3-benzoxazine-2,4(3H)-dione (1904 g, 9.64mol), ethyl 4-bromobutyrate (1313 mL, 9.18 mol), andN,N-dimethylacetamide (4700 mL) were charged under a nitrogen purge. Thereaction mixture was heated to 70° C. Sodium carbonate (1119 g, 10.55mol) was charged to the clear solution in five equal portions overapproximately 40 minutes. The reaction mixture was held at 70° C.overnight. The reaction was cooled to 55° C. The inorganic solids wereremoved by vacuum filtration through a sintered glass funnel. Thereaction flask was rinsed with 2B-ethanol (2000 mL) and this rinse usedto wash the filter cake. The reaction flask was cleaned with deionizedwater. The filtrate was returned to the clean reaction flask. Thefiltrate was cooled in an ice bath. Deionized water (9400 mL) was addedslowly with an addition funnel. The chilled mixture was allowed to stirovernight. The resulting solids were recovered by vacuum filtrationthrough a sintered glass funnel. The product cake was washed withdeionized water. The ethyl3-(4-butanoate)-7-chloro-2H-1,3-benzoxazine-2,4-(3H)-dione had a weightof 2476.0 g. The yield was 82.2%.

A 12 L, stainless steel reactor was equipped with an overhead stirrer,reflux condenser, thermocouple temperature read out, addition funnel,and heating mantle. The following reaction was run under a dry nitrogenatmosphere. Water (3 L) and ethyl3-(4-butanoate)-7-chloro-2H-1,3-benzoxazine-2,4-(3H)-dione (1118 g, 3.58mol) were charged to the reactor and stirring was started. A solution ofsodium hydroxide (574 g, 4.34 mol) in-water (2 L) was added slowly tothe reaction slurry. The reaction was heated to 70° C. for 6 hours, andthen allowed to cool slowly to ambient temperature. The reaction mixturewas filtered through a Buchner funnel.

A 22 L five neck round bottom flask was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, and anaddition funnel. Deionized water (1880 mL) and concentrated hydrochloricacid (1197 g, 12.04 mol) were charged to the reactor. The hydrolysatefrom above was added slowly via addition funnel to the acid solution.The pH of the resulting slurry was adjusted to 3 by adding additionalhydrochloric acid (160 mL, 1.61 mol) The product solids were collectedby filtration through a sintered glass funnel and dried in a vacuum ovenat 50° C. for 24 hours to give 1109.3 g of4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid as an off whitesolid. The yield was quantitative.

EXAMPLE 1d Preparation of Anhydrous Sodium4-[(2-Hydroxybenzoyl)amino]butanoate

A 22 L, five neck round bottom flask, was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, andheating mantle. The following reaction was run under a dry nitrogenatmosphere. Reagent acetone (13000 mL) and4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (500.0 g, 1.94 mol)were charged to the reactor and stirring was started. The reactionslurry was heated to 50° C. until a hazy brown solution was obtained.The warm solution was pumped through a warm pressure filter dressed withWhatman #1 paper into a clean 22 L reactor. The clear yellow filtratewas heated to 50° C. while stirring. Sodium hydroxide solution (50%aqueous; 155 g, 1.94 mol) was charged to the reactor while maintainingvigorous agitation. After the base addition was complete, the reactorwas heated to reflux (60° C.) for 2.5 hours and then allowed to coolslowly to ambient temperature. The product was isolated by vacuumfiltration through a sintered glass funnel and dried in a vacuum oven at50° C. for 24 hours to give 527.3 g of sodium4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yieldwas 97.2%.

EXAMPLE 1e Preparation of Sodium4-[(4-chloro-2-Hydroxybenzoyl)amino]butanoate

A 22 L flask was equipped with an overhead stirrer. Deionized water(2000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (380.0g, 1.47 mol) were added and stirring was started. A solution of sodiumhydroxide (59.0 g, 1.48 mol) in water (500 mL) was added to the reactor.Water (1500 mL) was added to the reactor, and the resulting slurry washeated until a complete solution was obtained. The reaction mixture wascooled to ambient temperature, and then concentrated to dryness underreduced pressure. The resulting solids were scraped from the flask andvacuum dried at 50° C. to give 401.2 g of sodium4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yieldwas 96.9%.

EXAMPLE 1f Preparation of Sodium 4-[(2-Hydroxybenzoyl)-amino]butanoateThrough the Isopropanol Solvate

A one liter, four neck round bottom flask was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, andheating mantle. The following reaction was run under a dry nitrogenatmosphere. Isopropanol (400 mL) and4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (25.0 g, 0.09 mol)were charged to the reactor and stirring was started. The reactionslurry was heated to 50° C. until a hazy brown solution was obtained.The warm solution was filtered through a warm pressure filter dressedwith Whatman #1 paper into a clean 1 L reactor. The clear yellowfiltrate was heated to 62° C. while stirring. Sodium hydroxide solution(50% aqueous; 7.2 g, 0.09 mol) was charged to the reactor whilemaintaining vigorous agitation. After the base addition was complete,the reactor was heated to reflux (72° C.) and then allowed to coolslowly to ambient temperature. The product was isolated by vacuumfiltration through a sintered glass funnel and vacuum dried at 50° C.for 24 hours to give 23.16 g of sodium4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yieldwas 92%.

EXAMPLE 1g Capsule Preparation

Capsules for primate dosing containing the monosodium salt of compound 1(as prepared in example 1d) and insulin were prepared as follows. Thecompound 1 monosodium salt and QA307X zinc insulin crystals human:proinsulin derived (recombinant DNA origin) (available from Eli-Lilly &Co. of Indianapolis, Ind.) were first screened through a 35 mesh Tylerstandard sieve and the required amount weighed. Screened compound 1monosodium salt and insulin were blended using geometric sieving methodin a suitably sized glass mortar. The materials in the mortar were mixedwell with a glass pestle. A spatula was used for scrapping the sides ofthe mortar. The resulting formulation was transferred to a plastic weighboat for capsule filling. The formulation was hand packaged into size #0Torpac hard gelatin capsules (available from Torpac, Inc. of Fairfield,N.J.). Each capsule fill weight was dependent on the individual animalweight. Capsules doses of compound 1 were 100 mg/kg, 75 mg/kg and 50mg/kg (as monosodium salt). Capsule doses of insulin were 0.25 to 0.5 mgper kg.

EXAMPLE 2 Insulin—Oral Delivery

A. Rat Studies Oral dosing (PO) compositions of delivery agent compound(prepared as in Example 1a or 1b as indicated below) and zinc humanrecombinant insulin (available from Calbiochem-Novabiochem Corp., LaJolla, Calif. (Catalog # 407694)) were prepared in deionized water.Typically, 500 mg of delivery agent compound was added to 1.5 ml ofwater. The free acid of the delivery agent compound was converted to thesodium salt by stirring the resultant solution and adding one equivalentof sodium hydroxide. The solution was vortexed, then heated (about 37°C.) and sonicated. The pH was adjusted to about 7 to 8.5 with NaOH orHCl. Additional NaOH was added, if necessary, to achieve uniformsolubility, and the pH re-adjusted. (For example, for compound 1a, atotal of 258.5 ml 10N NaOH was added to 501 mg compound in 1.5 ml water,final pH 7.73.) Water was then added to bring the total volume to about2.4 ml and vortexed. About 1.25 mg insulin from an insulin stocksolution (15 mg/ml made from 0.5409 g insulin and 18 ml deionized water,adjusting with HCl and NaOH to pH 8.15 and to obtain a clear solutionusing 40 ml concentrated HCl, 25 ml 10N NaOH and 50 ml 1N NaOH) wasadded to the solution and mixed by inverting. The final delivery agentcompound dose, insulin dose and dose volume amounts are listed below inTable 1.

The dosing and sampling protocols were as follows. Male Sprague-Dawleyrats weighing between about 200-250 g were fasted for 24 hours andadministered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. For oral dosing, an 11 cm Rusch 8 French catheter was adaptedto a 1 ml syringe with a pipette tip. The syringe was filled with dosingsolution by drawing the solution through the catheter, which was thenwiped dry. The catheter was placed down the esophagus leaving 1 cm oftubing past the incisors. Solution was administered by pressing thesyringe plunger.

Blood samples were collected serially from the tail artery, typically attime=15, 30, 60, 120 and 180 minutes after administration. Serum insulinlevels were determined with an Insulin ELISA Test Kit (Kit # DSL-10-1600from Diagnostic Systems Laboratories, Inc., Webster, Tex.), modifyingthe standard protocol in order to optimize the sensitivity and linearrange of the standard curve for the volumes and concentrations of thesamples used in the present protocol. Serum human insulin concentrations(μU/ml) were measured for each time point for each of the five animalsin each dosing group. The five values for each time point were averagedand the results plotted as serum insulin concentration versus time. Themaximum (peak) and the area under the curve (AUC) are reported below inTable 1. Previous experiments revealed no measurable levels of humaninsulin following oral dosing with human insulin alone.

TABLE 1 Insulin-Oral Delivery Mean Peak volume Compound Insulin SerumHuman dose Dose Dose Insulin Compound (ml/kg) (mg/kg) (mg/kg) (μU/ml ±SE) AUC 1a 1.0 200 0.5 1457 ± 268 58935 1b 1.0 200 0.5 183 ± 89 8674 1b1.0 200 0.5 136 ± 52 5533 1b 1.0 200 0.5 205 ± 61 7996 1b 1.0 200 0.5139 ± 43 5271B. Monkey Studies

All animal protocols adhered to the “Principles of Laboratory AnimalCare” and were Institutional Animal Care and Use Committee (IACUC)approved.

The dosing protocol for administering the capsules to each animal was asfollows. Baseline plasma samples were obtained from the animals prior todosing. Groups of four cynomolgus monkeys, two males and two females,weighing 2-3 kg were fasted for 4 hours prior to dosing and up to 2hours after dosing. The animals were anesthetized with an intramuscularinjection of 10 mg/kg ketamine hydrochloride immediately prior todosing. Each animal was administered varying doses of compound 1 (25-100mg/kg) in combination with varying doses of insulin 0.25-0.5 mg/kginsulin as 1 capsule. Water was available throughtout the dosing periodand 400 ml of juice was made available to the animal overnight prior todosing and throughout the dosing period. The animal was restrained in asling restraint. A capsule was placed into a pill gun, which is aplastic tool with a cocket plunger and split rubber tip to accommodate acapsule. The pill gun was inserted into the espophagus of the animal.The plunger of the pill gun was pressed to push the capsule out of therubber tip into the espophagus. The pill gun was then retracted. Theanimals mouth was held closed and approximately 5 ml reverse osmosiswater was administered into the mouth from the side to induce aswallowing reflex. The throat of the animal was rubbed further to inducethe swallowing reflex.

Citrated blood samples (1 mL each) were collected by venipuncture froman appropriate vein at 1 hour before dosing and at 10, 20, 30, 40, and50 minutes and 1, 1.5, 2, 3, 4, and 6 hours after dosing. Each harvestedplasma sample was divided into two portions. One portion was frozen at−80° C. and shipped to another location for insulin assay. The otherportion was used in the blood glucose assay. Four monkeys also receivedinsulin subcutaneously (0.02 mg/kg). Blood samples were collected andanalyzed as described above.

Insulin Assays. Serum insulin levels were measured using the InsulinELISA Test Kit (DSL, Webster, Tex.).

Glucose Assays. Blood glucose measurements were performed usingONETOUCH® Glucose Monitoring System from Live Scan Inc., Newtown, Pa.

The results are shown in Table 1A below.

TABLE 1A Insulin - Oral Delivery to Monkeys Mean Peak Compound InsulinSerum Human Mean Peak Blood Com- Dose Dose Insulin Glucose Reductionpound (mg/kg) (mg/kg) (μU/ml ± SE) (μU/ml ± SE) 1d 100 0.5 91.4 ± 45  52.3 ± 5.3  1d 50 0.5 124.1 ± 51.95  −61 ± 12.7 1d 25 0.5 87.14 ± 53.85−28.75 ± 21.59   1d 25 0.25 36.35 ± 32.3     −19 ± 10.21

EXAMPLE 3 Cromolyn—Oral Delivery

Dosing solutions containing a delivery agent compound (prepared as inExample 1b) and cromolyn, disodium salt (cromolyn) (Sigma, Milwaukee,Wis.) were prepared in deionized water. The free acid of the deliveryagent compound was converted to the sodium salt with one equivalent ofsodium hydroxide. This mixture was vortexed and placed in a sonicator(about 37° C.). The pH was adjusted to about 7-7.5 with aqueous NaOH.Additional NaOH was added, if necessary, to achieve uniform solubility,and the pH re-adjusted. The mixture was vortexed to produce a uniformsolution, also using sonication and heat if necessary. The deliveryagent compound solution was mixed with cromolyn from a stock solution(175 mg cromolyn/ml in deionized water, pH adjusted, if necessary, withNaOH or HCl to about 7.0, stock solution stored frozen wrapped in foil,then thawed and heated to about 30° C. before using). The mixture wasvortexed to produce a uniform solution, also using sonication and heatif necessary. The pH was adjusted to about 7-7.5 with aqueous NaOH. Thesolution was then diluted with water to the desired volume (usually 2.0ml) and concentration and stored wrapped in foil before use. The finaldelivery agent compound and cromolyn doses, and the dose volumes arelisted below in Table 2.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand were anesthetized with ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing and again as needed to maintainanesthesia. A dosing group of five animals was administered one of thedosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. Solution was administered by pressing the syringe plunger.

Blood samples were collected via the tail artery, typically at 0.25,0.5, 1.0 and 1.5 hours after dosing. Serum cromolyn concentrations weremeasured by HPLC. Samples were prepared as follows: 100 μl serum wascombined with 100 μl 3N HCl and 300 μl ethyl acetate in an eppendorftube. The tube was vortexed for 10 minutes and then centrifuged for 10minutes at 10,000 rpm. 200 μl ethyl acetate layer was transferred to aneppendorf tube containing 67 μl 0.1 M phosphate buffer. The tube wasvortexed for 10 minutes and then centrifuged for 10 minutes at 10,000rpm. The phosphate buffer layer was then transferred to an HPLC vial andinjected into the HPLC (column=Keystone Exsil Amino 150×2 mm i.d., 5 μm,100 Å (Keystone Scientific Products, Inc.); mobile phase=35% buffer(68mM KH₂PO₄ adjusted to pH 3.0 with 85% H₃PO₄)/65% acetonitrile; injectionvolume=10 μl; flow rate=0.30 ml/minute; cromolyn retention time=5.5minutes; absorbance detected at 240 nm). Previous studies indicatedbaseline values of about zero.

Results from the animals in each group were averaged for each time pointand the highest of these averages (i.e., mean peak serum cromolynconcentration) is reported below in Table 2.

TABLE 2 Cromolyn - Oral Delivery Mean Peak volume Compound Cromolynserum dose Dose Dose [cromolyn] ± Compound (ml/kg) (mg/kg) (mg/kg) SD(SE) 1b 1 200 25 0.70 ± 0.36 (0.16)

EXAMPLE 4 Recombinant Human Growth Hormone (rhGH)—Oral Delivery

Oral gavage (PO) dosing solutions of delivery agent compound (preparedas in Example 1a or 1b as indicated in Table 3 below) and rhGH wereprepared in phosphate buffer. The free acid of the delivery agentcompound was converted to the sodium salt with one equivalent of sodiumhydroxide. Typically, a solution of the compound was prepared inphosphate buffer and stirred, adding one equivalent of sodium hydroxide(1.0 N) when making the sodium salt. Additional NaOH was added, ifnecessary, to achieve uniform solubility, and the pH re-adjusted. Thefinal dosing solutions were prepared by mixing the compound solutionwith an rhGH stock solution (15 mg rhGH/ml made by mixing as powders 15mg rhGH, 75 mg D-mannitol, 15 mg glycine and 3.39 mg dibasic sodiumphosphate, then diluting with 2% glycerol) and diluting to the desiredvolume (usually 3.0 ml). The compound and rhGH doses and the dosevolumes are listed below in Table 3.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. Solution was administered by pressing the syringe plunger.

Blood samples were collected serially from the tail artery, typically attime=15, 30, 45 and 60 minutes after administration. Serum rHGHconcentrations were quantified by an rHGH immunoassay test kit (Kit #K1F4015 from Genzyme Corporation Inc., Cambridge, Mass.). Previousstudies indicated baseline values of about zero.

Results from the animals in each group were averaged for each timepoint. The maximum of these averages (i.e., the mean peak serum rhGHconcentration) is reported below in Table 3. (In the cases where nostandard deviation (SD) or standard error (SE) is given below, the fivesamples from each time period were pooled prior to assaying.)

TABLE 3 rhGH - Oral Delivery Volume Compound rhGH Mean Peak dose DoseDose Serum [rhGH] ± SD Compound (ml/kg) (mg/kg) (mg/kg) (SE) (ng/ml) 1a1 200 3 99.35 1a 1 200 3 42.62 1b 1 200 3 84.01 ± 73.57 (32.90) 1b 1 2003 50.44 ± 34.13 (15.26)

EXAMPLE 5 Interferon—Oral Delivery

Dosing solutions of delivery agent compound (prepared as in Example 1b)and human interferon (IFN) were prepared in deionized water. The freeacid of the delivery agent compound was converted to the sodium saltwith one equivalent of sodium hydroxide. Typically, a solution of thedelivery agent compound was prepared in water and stirred, adding oneequivalent of sodium hydroxide (1.0 N) when making the sodium salt. Thismixture was vortexed and placed in a sonicator (about 37° C.). The pHwas adjusted to about 7.0 to 8.5 with aqueous NaOH. The mixture wasvortexed to produce a uniform suspension or solution, also usingsonication and heat if necessary. Additional NaOH was added, ifnecessary, to achieve uniform solubility, and the pH re-adjusted. Thedelivery agent compound solution was mixed with an IFN stock solution(about 22.0 to 27.5 mg/ml in phosphate buffered saline) and diluted tothe desired volume (usually 3.0 ml). The final delivery agent compoundand IFN doses, and the dose volumes are listed below in Table 4.

The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. Solution was administered by pressing the syringe plunger.

Blood samples were collected serially from the tail artery, typically attime=0, 15, 30, 45, 60 and 90 minutes after administration. Serum IFNconcentrations were quantified using Cytoscreen Immunoassay Kit forhuman IFN-alpha (catalog # KHC4012 from Biosource International,Camarillo, Calif.). Previous studies indicated baseline values of aboutzero. Results from the animals in each group were averaged for each timepoint. The maximum of these averages (i.e., the mean peak serum IFNconcentration) is reported below in Table 4.

TABLE 4 Interferon - Oral Delivery Mean Peak Volume Compound IFN Serum[IFN] dose Dose Dose (ng/ml) ± Compound (ml/kg) (mg/kg) (mg/kg) SD (SE)1b 1.0 200 1.0 17.80 ± 13.52 (6.05)

The above-mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above detailed description. Allsuch obvious variations are within the fully intended scope of theappended claims.

1. A compound of the formula

or a salt thereof.
 2. A composition comprising: (A) at least one activeagent; and (B) a compound having the formula

a salt thereof, or a mixture thereof.
 3. The composition of claim 2,wherein the active agent is selected from the group consisting of abiologically active agent, a chemically active agent, and a combinationthereof.
 4. The composition of claim 3, wherein the biologically activeagent is at least one protein, polypeptide, peptide, hormone,polysaccharide, mucopolysaccharide, carbohydrate, or lipid.
 5. Thecomposition of claim 2, wherein the active agent is selected from thegroup consisting of: growth hormones, human growth hormones, recombinanthuman growth hormones, bovine growth hormones, porcine growth hormones,growth hormone-releasing hormones, interferons, α-interferon,β-interferon, γ-interferon, interleukin-1, interleukin-2, insulin,porcine insulin, bovine insulin, human insulin, human recombinantinsulin, insulin-like growth factor, insulin-like growth factor-1,heparin, unfractionated heparin, heparinoids, dermatans, chondroitins,low molecular weight heparin, very low molecular weight heparin, ultralow molecular weight heparin, calcitonin, salmon calcitonin, eelcalcitonin, human calcitonin; erythropoietin (EPO), atrial natureticfactor, antigens, monoclonal antibodies, somatostatin, proteaseinhibitors, adrenocorticotropin, gonadotropin releasing hormone,oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulatinghormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins,cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate,disodium chromoglycate, vancomycin, desferrioxamine, parathyroidhormone, fragments of parathyroid hormone, antimicrobials, anti-fungalagents, vitamins; and any combination thereof.
 6. The composition ofclaim 2, wherein the active agent is insulin, human growth hormone,interferon, cromolyn sodium or combinations thereof.
 7. The compositionof claim 2, wherein the active agent is insulin.
 8. The composition ofclaim 2, wherein the active agent is interferon.
 9. A dosage unit formcomprising: (A) the composition of claim 2; and (B) (a) an excipient (b)a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) acolorant, (g) a dosing vehicle, or (h) any combination thereof.
 10. Thedosage unit form of claim 9, wherein the active agent is selected fromthe group consisting of a biologically active agent, a chemically activeagent, and a combination thereof.
 11. The dosage unit form of claim 10,wherein the biologically active agent is a protein, polypeptide,peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, orlipid.
 12. The dosage unit form of claim 9, wherein the active agent isselected from the group consisting of: growth hormones, human growthhormones, recombinant human growth hormones, bovine growth hormones,porcine growth hormones, growth hormone-releasing hormones, interferons,α-interferon, β-interferon, γ-interferon, interleukin-1, interleukin-2,insulin, porcine insulin, bovine insulin, human insulin, humanrecombinant insulin, insulin-like growth factor, insulin-like growthfactor-1, heparin, unfractionated heparin, heparinoids, dermatans,chondroitins, low molecular weight heparin, very low molecular weightheparmn, ultra low molecular weight heparmn, calcitonin, salmoncalcitonin, eel calcitonin, human calcitonin; erythropoietin, atrialnaturetic factor, antigens, monoclonal antibodies, somatostatin,protease inhibitors, adrenocorticotropin, gonadotropin releasinghormone, oxytocin, leutinizing-hormone-releasing-hormone, folliclestimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim,prostaglandins, cyclosporin, vasopressin, cromolyn sodium, sodiumchromoglycate, disodium chromoglycate, vancomycin, desferrioxamine,parathyroid hormone, fragments of parathyroid hormone, antimicrobials,anti-fungal agents, vitamins; and any combination thereof.
 13. Thedosage unit form of claim 9, wherein the active agent is insulin, humangrowth hormone, interferon, cromolyn sodium or combinations thereof. 14.The dosage unit form of claim 9, wherein the active agent is insulin.15. The dosage unit form of claim 9, wherein the active agent isinterferon.
 16. The dosage unit form of claim 9, wherein the dosage unitform is in the form of a tablet, a capsule, a particle, a powder, asachet, or a liquid.
 17. The dosage unit form of claim 9, wherein thedosing vehicle is a liquid selected from the group consisting of water,25% aqueous propylene glycol, phosphate buffer, 1,2-propane diol,ethanol, and any combination thereof.
 18. A method for preparing acomposition comprising mixing: (A) at least one active agent; (B) thecompound of claim 1; and (C) optionally, a dosing vehicle.
 19. Anhydroussodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate.
 20. A compositioncomprising: (a) at least one active agent; and (b) the anhydrouscompound of claim
 19. 21. The composition of claim 20, wherein theactive agent is insulin.
 22. A solid oral dosage form comprising: (A)the composition of claim 21; and (B) (a) an excipient, (b) a diluent,(c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant,(g) a dosing vehicle, or (h) any combination thereof.
 23. Sodium4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate isopropanol solvate.
 24. Acomposition comprising: (a) at least one active agent; and (b)thecompound of claim
 23. 25. The composition of claim 24, wherein theactive agent is insulin.
 26. A solid oral dosage form comprising: (A)the composition of claim 25; and (B) (a) an excipient, (b) a diluent,(c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant,(g) a dosing vehicle, or (h) any combination thereof.
 27. Apharmaceutical composition comprising: (A) insulin; and (B) a compoundhaving the formula

or a salt thereof.